Catastrophic heart rhythm disorders are among the leading causes of death in the United States. The most dangerous of these arrhythmias is ventricular fibrillation, a disturbance in which disordered wave propagation causes a fatal disruption of the synchronous contraction of the ventricle. Although the exact mechanism for fibrillation is still being debated, one theory proposes that fibrillation is a state of spatiotemporal chaos consisting of the perpetual nucleation and disintegration of spiral waves (Chen et al., “Mechanism of Ventricular Vulnerability to Single Premature Stimuli in Open-Chest Dogs,” Circ Res 62:1991-209 (1988) and Witkowski et al., “Spatiotemporal Evolution of Ventricular Fibrillation,” Nature 392:78-82 (1998)), in association with a period doubling bifurcation of local electrical properties (Garfinkel et al., “Preventing Ventricular Fibrillation by Flattening Cardiac Restitution,” Proc Natl Acad Sci USA 97:6061-6 (2000); Gilmour et al., “Electrical Restitution, Critical Mass, and the Riddle of Fibrillation,” J Cardiovasc Electrophysiol 10:1087-9 (1999); Karma, A., “Electrical Alternans and Spiral Wave Breakup in Cardiac Tissue,” Chaos 4:461-72 (1994); and Panfilov, A., “Spiral Breakup as a Model of Ventricular Fibration,” Chaos 8:57-64 (1998)). Nucleation of the initiating spiral wave pair is caused by local conduction block (wave break) secondary to spatial heterogeneity of refractoriness in the ventricle (Arce et al., “Alternans and Higher-Order Rhythms in an Ionic Model of a Sheet of Ischemic Ventricular Muscle,” Chaos 10:411-26 (2000); Chen et al., “Mechanism of Ventricular Vulnerability to Single Premature Stimuli in Open-Chest Dogs,” Circ Res 62:1991-209 (1988); Sampson et al., “Simulation and Prediction of Functional Block in the Presence of Structural and Ionic Heterogeneity,” Am J Physiol 281:H2597-603 (2001); Winfree, When Time Breaks Down (Princeton, N.J.: Princeton University Press) (1987); and Witkowski et al., “Spatiotemporal Evolution of Ventricular Fibrillation,” Nature 392:78-82 (1998)). Until recently, spatial heterogeneity was thought to result solely from regional variations of intrinsic cellular electrical properties (Sampson et al., “Simulation and Prediction of Functional Block in the Presence of Structural and Ionic Heterogeneity,” Am J Physiol 281:H2597-603 (2001); and Yan et al., “Characteristics and Distribution of M Cells in Arterially Perfused Canine Left Ventricular Wedge Preparations,” Circulation 98:1921-7 (1998)) or from stimulation at more than one spatial location (Qu et al., “Mechanisms of Discordant Alternans and Induction of Reentry in Simulated Cardiac Tissue,” Circulation 102:1664-70 (2000); Watanabe et al., “Mechanisms for Discordant Alternans,” J Cardiovasc Electrophysiol 12:196-206 (2001); and Winfree, When Time Breaks Down (Princeton, N.J.: Princeton University Press) (1987)). However, it is now appreciated that purely dynamical heterogeneity can be sufficient to cause conduction block during single-site stimulation in both homogeneous one-dimensional models of canine heart tissue and in rapidly paced canine Purkinje fibres (Echebarria et al., “Instability and Spatiotemporal Dynamics of Alternans in Paced Cardiac Tissue,” Phys Rev Lett 88:208101 (2002) and Fox et al, “Spatiotemporal Transition to Conduction Block in Canine Ventricle,” Circ Res. 90:289-96 (2002)). A similar mechanism has been shown to precipitate conduction block and spiral break-up in models of homogeneous two-dimensional tissue (Fenton et al., “Multiple Mechanisms of Spiral Wave Breakup in a Model of Cardiac Electrical Activity,” Chaos 12:852-92 (2002)).
The period doubling bifurcation implicated in the transition to conduction block is manifest as alternans, a beat-to-beat long-short alternation in the duration of the cardiac action potential (Garfinkel et al., “Preventing Ventricular Fibrillation by Flattening Cardiac Restitution,” Proc Natl Acad Sci USA 97:6061-6 (2000); Gilmour et al., “Electrical Restitution, Critical Mass, and the Riddle of Fibrillation,” J Cardiovasc Electrophysiol 10:1087-9 (1999); Karma, A., “Electrical Alternans and Spiral Wave Breakup in Cardiac Tissue,” Chaos 4:461-72 (1994); Panfilov, A., “Spiral Breakup as a Model of Ventricular Fibration,” Chaos 8:57-64 (1998); and Watanabe et al., “Mechanisms for Discordant Alternans,”J Cardiovasc Electrophysiol 12:196-206 (2001)). Previous investigators have hypothesized that alternans can be accounted for by a simple uni-dimensional return map called the action potential duration restitution function (Chialvo et al., “Low Dimensional Chaos in Cardiac Tissue,” Nature 343:653-7 (1990); Chialvo et al., “Non-Linear Dynamics of Cardiac Excitation and Impulse Propagation,” Nature 330:749-52 (1987); Guevara et al., “Electrical Alternans and Period Doubling Bifurcations,” IEEE Comput Cardiol 562:167-70 (1984); and Nolasco et al., “A Graphic Method for the Study of Alternation in Cardiac Action Potentials,” J Appl Physiol 25:191-6 (1968)). This hypothesis assumes the duration D of an action potential depends only on its preceding rest interval I through some function ƒ(I) that is measured experimentally. If the D restitution function has a slope ≧1, then a period doubling bifurcation occurs for some value of the stimulus period T, where T=D+I. The velocity V at which an action potential propagates can also be described by a restitution function, where V=c(I).
It has also been shown previously that the combination of a steeply sloped action potential duration (“APD”) restitution function and a monotonically increasing conduction velocity (“CV”) restitution function is sufficient to produce dynamical conduction block during sustained pacing at a short cycle length (Fox et al, “Conduction Block in One-dimensional heart Fibers,” Phys. Rev. Lett. 89:198101 (2002); Fox et al, “Spatiotemporal Transition to Conduction Block in Canine Ventricle,” Circ Res. 90:289-96 (2002)). This observation may provide a generic mechanism for wave break and the onset of ventricular tachycardia and fibrillation. However, it is unlikely that the conditions used to demonstrate this phenomenon experimentally apply to the clinical situation, where the induction of ventricular tachyarrhythmias typically is associated with the interruption of normal cardiac rhythm by only a few premature beats. A single premature beat is sufficient to cause spatial heterogeneity in the form of discordant alternans (Watanabe et al., “Mechanisms for Discordant Alternans,” J Cardiovasc Electrophysiol 12:196-206 (2001)), but the conditions required for the development of conduction block in this setting have not been studied extensively.
Other studies, building on earlier theoretical work by Krinsky, Winfree and colleagues (Krinsky et al, “Votices with Linear Cores in Mathematical Models of Excitable Media,” Physica A 188:55-60 (1992) and Winfree, A., “Evolving Perspectives During 12 Years of Electrical Turbulence,” Chaos 8:1-20 (1998)) and experiments by Allessie (Allessie et al., “Circus Movement in Rabbit Atrial Muscle as a Mechanism of Tachycardia. III. The ‘Leading Circle’ Concept: a New Model of Circus Movement in Cardiac Tissue Without the Involvement of an Anatomical Obstacle,” Circ Res 41:9-18 (1977)), have suggested that spiral wave re-entry could be the ‘engine’ that drives ventricular fibrillation (“VF”) (Frazier et al., “Stimulus-Induced Critical Point. Mechanism for Electrical Initiation of Reentry in Normal Canine Myocardium,” J Clin Invest 83:1039-1052 (1989); Witkowski et al., “Spatiotemporal Evolution of Ventricular Fibrillation,” Nature 392:78-82 (1998); Weiss et al., “Chaos and the Transition to Ventricular Fibrillation: a New Approach to Antiarrhythmic Drug Evaluation,” Circulation 99:2819-2826 (1999); Chen et al., “Mechanism of Ventricular Vulnerability to Single Premature Stimuli in Open-Chest Dogs,” Circ Res 62:1191-1209 (1988); Gilmour et al., “Electrical Restitution, Critical Mass, and the Riddle of Fibrillation,” J Cardiovasc Electrophysiol 10:1087-1089 (1999); and Pertsov et al., “Spiral Waves of Excitation Underlie Reentrant Activity in Isolated Cardiac Muscle,” Circ Res 72:631-650 (1993)). Although there is substantial evidence that spiral wave re-entry contributes significantly to the induction and maintenance of VF, the exact mechanisms by which spiral waves sustain VF is currently being debated.
The present invention is directed towards correctly identifying the mechanisms (or more likely, mechanisms) by which spiral waves cause VF and the development of pharmacological approaches to VF treatment and prevention.